Ampril tablets 2.5 mg No. 30

Instructions for Ampril tablets 2.5 mg No. 30

Composition

active ingredient: ramipril;

1 tablet contains ramipril 2.5 mg;

excipients: sodium bicarbonate, lactose monohydrate, croscarmellose sodium, pregelatinized starch, sodium stearyl fumarate, Pigment Blend PB 22886 Yellow (contains lactose monohydrate, iron oxide yellow (E 172)).

Dosage form

Pills.

Main physicochemical properties: oval, flat tablets without a shell, yellow in color.

Pharmacotherapeutic group

Agents acting on the renin-angiotensin system. ACE inhibitors. Ramipril. ATC code C09A A05.

Pharmacological properties

Pharmacodynamics

Ramipril is a prodrug, after absorption it is broken down in the liver to form ramiprilat. Ramiprilat is a potent long-acting angiotensin-converting enzyme (ACE) inhibitor. ACE catalyzes the conversion of angiotensin I into the vasoconstrictor substance angiotensin II. ACE is an analogue of kininase, an enzyme that catalyzes the breakdown of bradykinin. Inhibition of ACE activity leads to a decrease in the concentration of angiotensin II, an increase in plasma renin activity, an increase in the action of bradykinin and a decrease in aldosterone secretion. The latter may lead to an increase in serum potassium.

In patients with arterial hypertension, the antihypertensive and hemodynamic effects of ramipril are due to the expansion of stable vessels and a decrease in total peripheral vascular resistance, as a result of which blood pressure gradually decreases. Heart rate is mostly unchanged. During long-term treatment, there is a decrease in left ventricular hypertrophy without affecting cardiac function. The hypotensive effect after a single dose is manifested 1-2 hours after administration, reaches a maximum within 3-6 hours and usually lasts for 24 hours. Ramipril is also an effective drug for the treatment of congestive heart failure. In patients with clinical signs of chronic heart failure after acute myocardial infarction, it reduces the risk of sudden death, progression of heart failure to severe or persistent heart failure and reduces the frequency of hospitalizations for heart failure.

According to published data, ramipril significantly reduces the incidence of myocardial infarction, stroke and reduces mortality from cardiovascular diseases in patients at increased risk due to cardiovascular disease (for example, active stage of coronary heart disease, previous stroke or peripheral vascular disease) or due to diabetes mellitus, who have at least one additional risk factor (microalbuminuria, hypertension, increased total cholesterol, low high-density lipoprotein cholesterol, smoking). The drug also reduces overall mortality and the need for revascularization and delays the onset and progression of congestive heart failure. In patients with diabetes mellitus, as well as other patients, ramipril significantly reduces the likelihood of microalbuminuria and the risk of developing nephropathy.

Pharmacokinetics

Ramipril is rapidly absorbed from the gastrointestinal tract. Absorption is 50-60% and is independent of food intake. Maximum serum concentrations are reached within 1 hour. The elimination half-life of ramipril is 1 hour.

Ramipril is metabolized in the liver. The main metabolite is ramiprilat, which is 6 times more potent as an ACE inhibitor than ramipril. In addition to ramiprilat, inactive metabolites (diketopiperazine ester and diketopiperazine acid, as well as compounds) have also been identified.

The maximum concentration of ramiprilat in the blood serum is reached 2-4 hours after administration, a constant concentration in the blood serum is reached after 4 days.

Approximately 73% of ramipril and 56% of ramiprilat are bound to serum proteins.

Ramipril and ramiprilat are mainly excreted in the urine (approximately 60%), mainly as metabolites, and less than 2% of the administered dose is excreted as unchanged ramipril.

Ramiprilat is eliminated in several stages. After administration of ramipril in therapeutic doses, the terminal half-life is 13 to 17 hours.

Animal studies have shown that this drug passes into breast milk.

Studies in healthy volunteers aged 65 to 76 years have shown that the kinetics of ramipril and ramiprilat in this category are the same as in young healthy volunteers.

In patients with renal insufficiency, the excretion of ramipril, ramiprilat and their metabolites is slowed down, therefore the dosage of ramipril should be adjusted depending on renal function (see "Method of administration and dosage").

In patients with hepatic insufficiency (possibly due to decreased hepatic esterase activity), the metabolic conversion of ramipril to ramiprilat may be slowed down and serum ramipril concentrations may increase.

Indication

Contraindication

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or to other ACE inhibitors (see section 6.1). History of angioedema (hereditary, idiopathic or previously treated with ACE inhibitors or angiotensin II receptor antagonists). Significant bilateral renal artery stenosis or stenosis of the artery to a solitary functioning kidney. Pregnant women or women planning to become pregnant (see section 6.2). Ramipril should not be used in patients with hypotension or haemodynamically unstable conditions. It should not be used in combination with aliskiren-containing products, in patients with diabetes mellitus or moderate or severe renal impairment (GFR < 60 ml/min). The concomitant use of ACE inhibitors and extracorporeal treatments that result in contact of blood with negatively charged surfaces should be avoided, as such use may lead to severe anaphylactoid reactions. Such extracorporeal treatments include dialysis or hemofiltration using certain membranes with high hydraulic permeability (e.g. polyacrylonitrile) and low-density lipoprotein apheresis using dextran sulfate.

Interaction with other medicinal products and other types of interactions

Contraindicated combinations.

Extracorporeal therapy methods that result in contact of blood with negatively charged surfaces, such as dialysis or hemofiltration using certain high flux membranes (e.g. polyacrylonitrile membranes) and low density lipoprotein apheresis using dextran sulfate - due to the increased risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is necessary, the use of a different dialysis membrane or the use of a different class of antihypertensive agents should be considered.

The combined use of ramipril with aliskiren-containing medicinal products is contraindicated in patients with diabetes mellitus or moderately severe renal impairment and is not recommended for other patient categories (see sections "Contraindications" and "Special warnings and precautions for use").

Combinations requiring precautions.

Potassium salts, heparin, potassium-sparing diuretics and other active substances that increase plasma potassium levels (including angiotensin II antagonists, trimethoprim, tacrolimus, ciclosporin). Hyperkalaemia may occur, therefore careful monitoring of plasma potassium levels is necessary.

Antihypertensive drugs (e.g. diuretics) and other substances that may lower blood pressure (e.g. nitrates, tricyclic antidepressants, anaesthetics, alcohol, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin). An increased risk of arterial hypotension should be expected (see section "Special warnings and precautions for use" for diuretics).

Vasopressor sympathomimetics and other substances (e.g. isoproterenol, dobutamine, dopamine, epinephrine) that may reduce the antihypertensive effect of Ampril®. Close monitoring of blood pressure is recommended.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that may cause changes in the blood picture. Increased likelihood of hematological reactions (see section "Special instructions").

Lithium salts: ACE inhibitors may reduce lithium excretion, which may lead to increased lithium toxicity. Lithium levels should be carefully monitored.

Antidiabetic agents, including insulin. Hypoglycemic reactions may occur. Close monitoring of blood glucose levels is recommended.

mTOR (target of rapamycin in cells) inhibitors or DPP-IV inhibitors. An increased risk of angioedema may occur in patients taking concomitant medications such as (temsirolimus, everolimus, sirolimus) or vildagliptin. Particular caution should be exercised when initiating treatment in these patients.

Salt. Excessive salt consumption may weaken the hypotensive effect of the drug.

Specific hyposensitization. ACE inhibition increases the likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom. It is believed that this effect may also be observed for other allergens.

Application features

Special categories of patients.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with aliskiren-containing medicinal products.

Dual blockade of the renin-angiotensin-aldosterone system through the combined use of Ampril® and aliskiren is not recommended, as there is an increased risk of developing arterial hypotension, hyperkalemia, and changes in renal function.

The combined use of aliskiren and Ampril® is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min) (see section "Contraindications").

Patients at particular risk of hypotension.

Patients with a strongly activated renin-angiotensin-aldosterone system. Patients with a strongly activated renin-angiotensin-aldosterone system are at risk of a sudden significant fall in blood pressure and deterioration of renal function due to ACE inhibition, particularly when an ACE inhibitor or concomitant diuretic is given for the first time or when the dose is increased for the first time. A strongly activated renin-angiotensin-aldosterone system, requiring medical supervision, including regular monitoring of blood pressure, may be expected, for example, in patients:

with severe arterial hypertension; with decompensated congestive heart failure; with hemodynamically significant obstruction to the inflow or outflow of blood from the left ventricle (for example, with aortic or mitral valve stenosis); with unilateral renal artery stenosis in the presence of a second functioning kidney; in whom fluid or electrolyte depletion exists or may develop (including those receiving diuretics); with cirrhosis of the liver and/or ascites; in whom extensive surgery is performed or during anesthesia with drugs that cause arterial hypotension.

It is generally recommended that dehydration, hypovolemia, or electrolyte depletion be corrected before treatment is initiated (however, for patients with heart failure, such corrective measures should be applied with consideration of the risk of volume overload).

In patients with impaired liver function, the response to treatment with Ampril® may be either enhanced or reduced. In addition, in patients with severe cirrhosis of the liver, accompanied by edema and/or ascites, the activity of the renin-angiotensin system may be significantly increased; therefore, special caution should be exercised when treating these patients.

Transient or persistent heart failure after myocardial infarction.

Patients at risk of cardiac or cerebral ischemia in the event of acute arterial hypotension. Special medical supervision is required in the initial phase of treatment.

Elderly patients: See section "Method of administration and dosage".

Surgery: If possible, treatment with angiotensin-converting enzyme inhibitors such as ramipril should be discontinued 1 day before surgery.

Monitoring of renal function. Renal function should be assessed before and during treatment and the dose adjusted, especially in the first weeks of treatment. Particularly careful monitoring is required in patients with impaired renal function (see section "Method of administration and dosage"). There is a risk of deterioration of renal function, especially in patients with congestive heart failure or after kidney transplantation.

Angioedema: Angioedema has been reported in patients treated with ACE inhibitors, including ramipril (see section 4.8). This risk may be increased in patients taking concomitant medications such as mTOR (target of rapamycin in cells) inhibitors (temsirolimus, everolimus, sirolimus) or vildagliptin.

In case of angioedema, Ampril® should be discontinued. Emergency treatment should be initiated immediately. The patient should be under medical supervision for at least 12-24 hours and may be discharged after complete resolution of symptoms.

Cases of intestinal angioedema have been reported in patients treated with ACE inhibitors, including Ampril (see section 4.8). These patients presented with abdominal pain (with or without nausea/vomiting).

Electrolyte balance control. Hyperkalemia. Hyperkalemia has been observed in some patients treated with ACE inhibitors, including Ampril®. Patients at risk for hyperkalemia include patients with renal insufficiency, patients over 70 years of age, patients with uncontrolled diabetes mellitus, patients taking potassium salts, potassium-sparing diuretics, and other active substances that increase plasma potassium levels, or patients with conditions such as dehydration, acute cardiac decompensation, metabolic acidosis. If the combined use of the above drugs is considered appropriate, regular monitoring of plasma potassium levels is recommended (see section "Interaction with other medicinal products and other types of interactions").

Electrolyte balance monitoring. Hyponatremia. Syndrome of inappropriate antidiuretic hormone secretion with subsequent hyponatremia has been observed in some patients treated with ramipril. Regular monitoring of serum sodium levels is recommended in the elderly and in other patients at risk of hyponatremia.

Neutropenia/agranulocytosis. Cases of neutropenia/agranulocytosis, as well as thrombocytopenia and anemia have been observed rarely. Bone marrow suppression has also been reported. Monitoring of the white blood cell count is recommended to detect possible leukopenia. More frequent monitoring is advisable at the beginning of treatment and in patients with impaired renal function, concomitant collagen disease (e.g. systemic lupus erythematosus or scleroderma) or those taking other medicinal products that may cause changes in the blood picture (see sections “Interaction with other medicinal products and other forms of interaction” and “Adverse reactions”).

Ethnic differences. ACE inhibitors cause angioedema more frequently in black patients than in non-blacks. As with other ACE inhibitors, the antihypertensive effect of ramipril may be less pronounced in black patients than in non-blacks. This may be because black hypertensive patients tend to have low-renin hypertension.

Cough. Cough has been reported with ACE inhibitors. The cough is typically non-productive, persistent, and resolves after discontinuation of therapy. The possibility of cough due to ACE inhibitors should be considered in the differential diagnosis of cough.

Special warnings regarding inactive ingredients

The drug contains lactose, so it should not be used in patients with rare hereditary disorders of galactose deficiency or glucose-galactose malabsorption syndrome.

Ability to influence reaction speed when driving vehicles or other mechanisms

Some side effects (certain symptoms of low blood pressure, such as dizziness or vertigo) may affect the ability to drive or operate machinery. Patients should be advised not to drive or operate hazardous machinery until they are sure that they respond normally to the treatment.

Use during pregnancy or breastfeeding

Pregnancy: The drug should not be used by pregnant women or women planning to become pregnant.

If pregnancy is confirmed during treatment with the drug, its use must be stopped immediately and, if necessary, therapy with another drug approved for use in pregnant women should be prescribed.

Breastfeeding. Due to the lack of information regarding the use of ramipril during breastfeeding (see section "Pharmacological properties"), this drug is not recommended for use in breast-feeding women and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while breastfeeding a newborn or preterm infant.

Method of administration and doses

The dosage and period of treatment depend on the patient's condition, the need for concomitant treatment and are always determined by the doctor.

It is recommended to take the drug at the same time every day. The drug can be taken before, during and after meals, as food intake does not affect the bioavailability of the drug. The tablets should be swallowed whole with water (approximately ½ cup). They should not be chewed or crushed.

Adults.

Patients taking diuretics. At the beginning of treatment with the drug, hypotension may occur, the development of which is more likely in patients who are simultaneously receiving diuretics. In such cases, caution is recommended, since these patients may experience a decrease in BCC and / or electrolytes.

It is advisable to discontinue the diuretic 2-3 days before starting treatment with ramipril, if possible (see section "Special warnings and precautions for use").

In patients with arterial hypertension who cannot discontinue the diuretic, treatment with ramipril should be initiated at a dose of 1.25 mg. Renal function and blood potassium levels should be closely monitored. Subsequent dosage should be adjusted according to the target blood pressure.

The dose should be selected individually, depending on the characteristics of the patient's condition (see section "Special instructions for use") and the results of control blood pressure measurements. Ramipril can be used as monotherapy or in combination with other classes of antihypertensive drugs.

Initial dose: Treatment with the drug should be initiated gradually, starting with the recommended initial dose of 2.5 mg per day.

In patients with a strongly activated renin-angiotensin-aldosterone system, a significant decrease in blood pressure may occur after the initial dose. In such patients, the recommended starting dose is 1.25 mg and treatment should be initiated under medical supervision (see section 4.4).

Dose titration and maintenance dose. The dose may be doubled every 2-4 weeks until the target blood pressure is reached; the maximum dose is 10 mg per day. The drug should usually be taken once daily.

Prevention of cardiovascular diseases.

Initial dose. The recommended initial dose of the drug is 2.5 mg once a day.

Dose titration and maintenance dose. Depending on individual tolerability, the dose should be increased gradually. It is recommended to double the dose after 1-2 weeks of treatment, and then - after another 2-3 weeks - increase it to the target maintenance dose of 10 mg 1 time per day.

Also see above for dosing information for patients receiving diuretics.

Treatment of kidney disease.

In patients with diabetes and microalbuminuria.

Initial dose. The recommended initial dose of the drug is 1.25 mg once a day.

Dose titration and maintenance dose. Depending on individual tolerability of the drug, the dose should be increased during further treatment. After 2 weeks of treatment, it is recommended to double the single daily dose to 2.5 mg, and then to 5 mg after another 2 weeks of treatment.

In patients with diabetes and at least one cardiovascular risk factor.

Initial dose. The recommended initial dose of the drug is 2.5 mg once a day.

Dose titration and maintenance dose. Depending on individual tolerability of the drug, the dose should be increased during further treatment. After 1-2 weeks of treatment, it is recommended to double the daily dose of the drug to 5 mg, and then to 10 mg after another 2-3 weeks of treatment. The target daily dose is 10 mg.

In patients with non-diabetic nephropathy, as evidenced by macroproteinuria ≥ 3 g/day.

Initial dose. The recommended initial dose of the drug is 1.25 mg once a day.

Dose titration and maintenance dose. Depending on the individual patient's tolerance of the drug, the dose should be increased during further treatment. After 2 weeks of treatment, it is recommended to double the single daily dose to 2.5 mg, and then to 5 mg after another 2 weeks of treatment.

Heart failure with clinical manifestations.

Initial dose: For patients stabilized on diuretic therapy, the recommended initial dose is 1.25 mg/day.

Dose titration and maintenance dose. The dose of the drug should be titrated by doubling it every 1-2 weeks until a maximum daily dose of 10 mg is reached. It is advisable to divide the dose into 2 doses.

Secondary prevention after acute myocardial infarction in the presence of heart failure.

Initial dose. 48 hours after the onset of myocardial infarction, patients who are clinically and hemodynamically stable should be given an initial dose of 2.5 mg twice daily for 3 days. If the initial dose of 2.5 mg is poorly tolerated, a dose of 1.25 mg twice daily should be used for 2 days, followed by an increase to 2.5 mg and 5 mg twice daily. If the dose cannot be increased to 2.5 mg twice daily, treatment should be discontinued.

Also see above for dosing information for patients receiving diuretics.

Dose titration and maintenance dose. Subsequently, the daily dose should be increased by doubling it at intervals of 1-3 days until the target maintenance dose of 5 mg 2 times a day is reached.

Whenever possible, the maintenance daily dose should be divided into 2 doses.

If the dose cannot be increased to 2.5 mg twice daily, treatment should be discontinued. Experience in the treatment of patients with severe (NYHA class IV) heart failure immediately after myocardial infarction is still insufficient. If a decision is nevertheless made to treat such patients with this drug, it is recommended to start therapy with a dose of 1.25 mg once daily and any increase should be carried out with extreme caution.

Special categories of patients.

if creatinine clearance is ≥ 60 ml/min, there is no need to adjust the initial dose (2.5 mg/day), and the maximum daily dose is 10 mg; if creatinine clearance is 30-60 ml/min, there is no need to adjust the initial dose (2.5 mg/day), and the maximum daily dose is 5 mg; if creatinine clearance is 10-30 ml/min, the initial daily dose is 1.25 mg/day, and the maximum daily dose is 5 mg; patients with arterial hypertension on hemodialysis: ramipril is excreted to a small extent during hemodialysis; the initial dose is 1.25 mg, and the maximum daily dose is 5 mg; the drug should be taken a few hours after the hemodialysis session.

Patients with impaired hepatic function (see section "Pharmacological properties"). Treatment with the drug in patients with impaired hepatic function should be initiated under close medical supervision, and the maximum daily dose in such cases should be 2.5 mg.

Elderly patients: The initial dose should be lower and subsequent dose titration should be more gradual because of the higher likelihood of adverse effects, especially in very elderly and debilitated patients. In such cases, a lower initial dose of 1.25 mg ramipril should be prescribed.

Children

Ramipril is not recommended for use in children, as there is insufficient data on the efficacy and safety of ramipril in such patients.

Overdose

Overdose may cause excessive peripheral vasodilation (accompanied by severe hypotension, shock), bradycardia, electrolyte imbalance and renal failure.

If hypotension occurs, the patient should be placed in a horizontal position, with the head placed on a low pillow, and the legs raised. If necessary, it is recommended to increase the plasma volume by infusion of 0.9% sodium chloride solution. After taking a large number of tablets, it is recommended to perform gastric lavage and administer adsorbents and sodium sulfate (in the first 30 minutes, if possible). It is necessary to carefully monitor blood pressure, renal function and serum potassium. In case of hypotension, in addition to volume and salt compensation, an alpha-1 adrenergic receptor agonist (e.g. noradrenaline, dopamine) and angiotensin II (angiotensin amide) can be administered.

The effectiveness of dialysis in treating intoxication has not been proven.

Adverse reactions

The safety profile of the drug includes data on persistent cough and reactions caused by arterial hypotension. Serious adverse reactions include angioedema, hyperkalemia, impaired liver or kidney function, pancreatitis, severe skin reactions and neutropenia/agranulocytosis.

Within each group, adverse reactions are presented in order of decreasing seriousness.

Cardiac disorders: myocardial ischemia, including angina pectoris or myocardial infarction; tachycardia; arrhythmia; palpitations; peripheral edema.

Blood and lymphatic system disorders: eosinophilia, decreased white blood cell count (including neutropenia or agranulocytosis), decreased red blood cell count, decreased hemoglobin level, decreased platelet count, bone marrow failure, pancytopenia, hemolytic anemia.

Nervous system: headache, dizziness, vertigo, paresthesia, ageusia, dysgeusia, tremor, balance disorders, cerebral ischemia, including ischemic stroke and transient ischemic attack; impaired psychomotor functions; burning sensation; parosmia.

From the organs of vision: visual disturbances, including blurred vision, conjunctivitis.

From the side of the organs of hearing and labyrinth: hearing impairment, tinnitus.

Respiratory, thoracic and mediastinal disorders: non-productive irritating cough, bronchitis, sinusitis, dyspnea, nasal congestion, bronchospasm, including exacerbation of asthma.

Gastrointestinal: gastrointestinal inflammation, indigestion, abdominal discomfort, dyspepsia, diarrhea, nausea, vomiting, pancreatitis (in isolated cases, fatal outcomes have been reported with the use of ACE inhibitors), increased pancreatic enzymes, angioedema of the small intestine, upper abdominal pain, including gastritis, constipation, dry mouth, glossitis, aphthous stomatitis.

On the part of the kidneys and urinary tract: impaired renal function, including acute renal failure; increased diuresis, worsening of background proteinuria, increased blood urea; increased blood creatinine.

Skin and subcutaneous tissue disorders: rash, particularly maculopapular, angioedema; in exceptional cases, airway obstruction due to angioedema, which may be fatal; pruritus, hyperhidrosis, exfoliative dermatitis, urticaria, onycholysis, photosensitivity reaction, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, exacerbation of psoriasis, psoriatic dermatitis, pemphigoid or lichenoid exanthema or enanthema, alopecia.

Musculoskeletal and connective tissue disorders: muscle spasms, myalgia, arthralgia. Endocrine disorders: syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Vascular disorders: hypotension, orthostatic hypotension, syncope, flushing, vascular stenosis, hypoperfusion, vasculitis, Raynaud's phenomenon.

General disorders: chest pain, fatigue, pyrexia, asthenia.

On the part of the immune system: anaphylactic and anaphylactoid reactions, increased levels of antinuclear antibodies.

Hepatobiliary disorders: increased levels of liver enzymes and/or bilirubin conjugates, cholestatic jaundice, liver cell damage, acute liver failure, cholestatic or cytolytic hepatitis (in very exceptional cases - fatal).

Reproductive system and breast disorders: transient erectile impotence, decreased libido, gynecomastia.

On the part of the psyche: decreased mood, anxiety, nervousness, restlessness, sleep disturbances, including drowsiness, a state of confusion, impaired attention.

Expiration date

3 years.

Storage conditions

Store at a temperature not exceeding 25 °C in the original packaging to protect from moisture. Keep out of the reach of children.

Packaging

10 tablets in a blister; 3 blisters in a cardboard box.

Vacation category

According to the recipe.

Producer

KRKA, dd, Novo mesto, Slovenia.

Location of the manufacturer and its business address

Smarjeska cesta 6, 8501 Novo mesto, Slovenia.